CN103936733A - Aaptamine alkaloid compound extracted from aaptos and application thereof to preparation of antitumor medicines - Google Patents

Aaptamine alkaloid compound extracted from aaptos and application thereof to preparation of antitumor medicines Download PDF

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Publication number
CN103936733A
CN103936733A CN201410180478.7A CN201410180478A CN103936733A CN 103936733 A CN103936733 A CN 103936733A CN 201410180478 A CN201410180478 A CN 201410180478A CN 103936733 A CN103936733 A CN 103936733A
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acid
methylene dichloride
alkaloid compound
extract
aaptamine
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CN103936733B (en
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林厚文
于豪冰
杨帆
焦伟华
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Second Military Medical University SMMU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

The invention relates to the technical field of marine organisms and medicines and provides an aaptamine alkaloid compound extracted, separated and purified from a marine animal aaptos originating from surrounding waters of the Xisha Islands. The chemical structure of the aaptamine alkaloid compound is shown in a formula (I) as shown in the specification. In-vitro activity tests prove that the compound has obvious inhibitory activity on various tumor cells such as human acute leukemic cells HL60, human chronic leukemic cells K562, human breast cancer cells MCF-7, human nasopharyngeal cancer cells KB, human liver cancers Hep G2, human colon cancer cells HT-29 and the like and can be used for preparing antitumor medicines.

Description

From dredging a kind of aaptamine alkaloid compound of extracting sponge and in the application of preparing in antitumor drug
Technical field
The present invention relates to marine organisms and medical technical field, be specifically related to a kind of a kind of new bio alkaloid compound obtaining through extraction, separation and purification and preparing the application in antitumor drug from originate from the thin sponge Aaptos aaptos of marine animal of sea area near Xisha Islands.
Background technology
Sponge is a kind of multicellular animals of low grade, and it is widely distributed, and often contains the secondary metabolite with anti-tumor activity that a lot of structures are rare, is therefore the first-selected marine organisms research object of marine natural product chemistry man always.
Medicine source material of the present invention is dredged sponge Aaptos aaptos and is belonged to the tough sponge order of ordinary guiding principle (Demospongiae) (Hardromerida) Suberitidae (Suberitidae) sponge, originates from sea area near Xisha Islands.From this genus sponge, separate and obtained some alkaloid compounds, these alkaloid compounds have shown certain anti-tumor activity, as separated the Suberitine B and the Suberitine D that obtain from A.suberitoides, mouse leukemia cell P388 is shown to stronger cytotoxic activity, IC 50value is respectively 1.8 and 3.5 μ M (referring to document: Liu C-X, Tang X-L, Li P-L, Li G-Q, Suberitine A-D, Four New Cytotoxic Dimeric Aaptamine Alkaloids from theMarine Sponge Aaptos suberitoides.Organic Letters2012,14 (8), 1994-1997.).
From this genus sponge, separate but so far there are no the aaptamine Alkaloid C that obtains having anti-tumor activity 16h 17n 3o 2report.
Summary of the invention
The object of the invention is to the new alkaloid compound obtaining through extraction, separation and purification from dredge sponge Aaptos aaptos, another object of the present invention is to provide extracting method and the medicinal use of this new compound.
A first aspect of the present invention, be to provide the new alkaloid compound with anti-tumor activity of a kind of thin sponge Aaptos aaptos that comes from Chinese sea area near Xisha Islands, it is a kind of aaptamine alkaloid compound, or its pharmaceutical salts, its chemical structure is as shown in formula I:
Formula I compound of the present invention, chemical name 3-isobutylamino demethyl (oxy) aaptamine molecular formula is C 16h 17n 3o 2.
A kind of aaptamine alkaloid compound of the present invention, or its pharmaceutical salts, described pharmaceutical salts is organic acid, inorganic acid salt and alkali salt.
Described mineral acid refers to hydrochloric acid, sulfuric acid, phosphoric acid, bisphosphate, Hydrogen bromide or nitric acid etc.;
Described organic acid refers to acetic acid, toxilic acid, fumaric acid, tartrate, succsinic acid, lactic acid, tosic acid, Whitfield's ointment or oxalic acid etc.;
Described alkali refers to lithium hydroxide, sodium hydroxide, calcium hydroxide, potassium hydroxide, ammoniacal liquor, sodium carbonate, sodium bicarbonate etc.
A second aspect of the present invention, has been to provide the preparation method of above-mentioned aaptamine alkaloid compound, and this preparation method comprises:
1. prepare total extract:
After dry thin sponge Aaptos aaptos (A.aaptos) is pulverized, with 95% ethanol cold soaking extraction, obtain extracting solution, extracting solution is concentrated to obtain to medicinal extract, add methylene dichloride to extract, obtain methylene dichloride total extract;
2. separation and purification:
1) prepare crude extract: by 90% methyl alcohol suspendible for methylene dichloride total extract, after normal hexane degreasing, add water the methanol concentration of suspension is adjusted to 60%, with dichloromethane extraction, concentrated extract obtains methylene dichloride crude extract;
2) separation and purification: by methylene dichloride crude extract through vacuum liquid chromatography (VLC), with methyl alcohol: methylene dichloride=100:1,80:1,60:1,50:1,30:1,20:1,10:1,8:1,5:1,1:1,0:1 is that solvent carries out gradient elution, and according to TLC thin-layer chromatography, colour developing merges similar flow point, obtains 7 component Fr.A – G;
3) component Fr.D is carried out to vacuum liquid chromatography (VLC), with methyl alcohol: methylene dichloride=60:1,50:1,30:1,15:1,10:1,8:1,5:1,0:1 is that solvent carries out gradient elution, and according to TLC thin-layer chromatography, colour developing merges similar flow point, obtains 7 component Fr.D1 – D7;
4) component Fr.D3 component is carried out to positive, reversed-phase column chromatography repeatedly, obtain the compounds of this invention C finally by RP-HPLC (detection wavelength is 244nm for 50% acetonitrile/water, flow velocity 2mL/min, and retention time is 16.3 minutes) 16h 17n 3o 2.
A third aspect of the present invention, is to provide above-mentioned aaptamine alkaloid compound, or its pharmaceutical salts, in the application of preparing in antitumor drug.
Activity test in vitro proves, the compounds of this invention is to people's acute leukemia cells HL60, people's chronic leukemia cell K562, human breast cancer cell MCF-7, KB cell KB, the multiple different tumour cells such as people's liver cancer Hep G2 and human colon cancer cell HT-29 all have certain inhibition activity.
Wherein to people's acute leukemia cells HL60, people's chronic leukemia cell K562, human breast cancer cell MCF-7, KB cell KB, the IC of people's liver cancer Hep G2 and human colon cancer cell HT-29 50value is respectively 0.28,0.46,2.26,1.13,1.02 and 8.48 μ M.Therefore can be used for preparing antitumor drug.
The compounds of this invention preparation method is simple, and anti-tumor activity is remarkable.The present invention provides new lead compound for researching and developing new antitumor drug, is the scientific basis that developed China Ocean Medicinal Resource Supply.
Embodiment
Below in conjunction with embodiments of the invention, enforcement of the present invention is elaborated; following examples are to implement under taking technical solution of the present invention as prerequisite; provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
The embodiment of the present invention thin sponge Aaptos aaptos used picks up from sea area near Xisha Islands in June, 2007, identified by professor Li Jinhe of the Institute of Oceanology of the Chinese Academy of Sciences, Sample preservation is in marine drug research department of attached Long March hospital of The 2nd Army Medical College, and sample number into spectrum is OLS.The present invention also can adopt other thin sponges to prepare compound of the present invention or prepare compound of the present invention by the method for synthetic.
Embodiment 1. prepares the compounds of this invention
1, prepare methylene dichloride crude extract
Get the thin sponge 2.3kg after drying and crushing, with 95% ethanol 15L diacolation extraction 4 times, each 3 days, united extraction liquid, extracting solution obtains medicinal extract through concentrating under reduced pressure, extract with dichloromethane solution, obtain methylene dichloride total extract, by 90% methyl alcohol suspendible for methylene dichloride total extract, with after normal hexane degreasing, add water the methanol concentration of suspension is adjusted to 60%, use dichloromethane extraction 3 times, concentrated extract obtains methylene dichloride crude extract 84.4g;
2, separation and purification
1) separation and purification: by methylene dichloride crude extract through the VLC column chromatography that reduces pressure, with methyl alcohol: methylene dichloride=100:1,80:1,60:1,50:1,30:1,20:1,10:1,8:1,5:1,1:1,0:1 is that solvent carries out gradient elution, and according to TLC thin-layer chromatography, colour developing merges similar flow point, obtains 7 component Fr.A – G;
2) component Fr.D is carried out to VLC decompression column chromatography, with methyl alcohol: methylene dichloride=60:1,50:1,30:1,15:1,10:1,8:1,5:1,0:1 is that solvent carries out gradient elution, and according to TLC thin-layer chromatography, colour developing merges similar flow point, obtains 7 component Fr.D1 – D7;
2) component Fr.D3 component is carried out to positive, reversed-phase column chromatography repeatedly, obtain the compounds of this invention C finally by RP-HPLC (detection wavelength is 244nm for 50% acetonitrile/water, flow velocity 2mL/min, and retention time is 16.3 minutes) 16h 17n 3o 2.
3, Structural Identification
The compounds of this invention C 16h 17n 3o 2through various modern spectroscopic techniquess such as NMR, HRESIMS, IR, UV, determine Compound C 16h 17n 3o 2chemical structure.
The compounds of this invention C 16h 17n 3o 2: orange solid; 5-5.50 (c0.15, MeOH); UV (MeOH) (log ε) λ max203.4 (0.35), 247.2 (0.15), 277.0 (0.10) nm; IR (KBr) ν max3367,3053,2959,2928,2870,1725,1645,1615,1566,1545,1462,1388,1340,1314,1274,1203,1176,1145,1105,1061,1004,967,923,872,826,733,693cm -1; HRESIMS m/z284.1397[M+H] +(calcd for C 16h 18n 3o 2, 284.1399). 1hand 13c nuclear magnetic resonance spectrum data are in table 1.
Table 1 Compound C 16h 17n 3o 2nuclear magnetic resonance spectrum data
aMeasured?at600MHz?in?CDCl 3； bMeasured?at150MHz?in?CDCl 3.
The anti tumor activity in vitro experiment of embodiment 2 the compounds of this invention:
To the compounds of this invention C 14h 13n 3o 3carried out anticancer experiment in vitro, tumor cell line used is as follows:
People's acute leukemia cells HL60 (HL60), purchased from ATCC, is for No. ATCC CCL-240;
People's chronic leukemia cell K562 (K562), purchased from ATCC, is for No. ATCC CCL-243;
Human breast cancer cell MCF-7 (MCF-7), purchased from ATCC, is for No. ATCC HTB-22;
KB cell KB (KB), purchased from ATCC, is for No. ATCC CCL-17;
People's liver cancer Hep G2 (Hep G2), purchased from ATCC, is for No. ATCC HB-8065;
Human colon cancer cell HT-29 (HT-29), purchased from ATCC, is for No. ATCC HTB-38.
People's acute leukemia cells HL60 and people's chronic leukemia cell K562, two kinds of clone all in the RPMI-1640 substratum of the foetal calf serum (FBS) of 37 DEG C of 10% non-dialysis suspension growth cultivate, in substratum, add the L-glutaminate of 2mM, penicillin 100 units/mL and 10 μ g/mL Streptomycin sulphates.For cell growth inhibition analysis, HL60 and K562 cell are arranged on 1 × 10 5individual cells/well, in Costar company 24 orifice plates.It is interference-free that cell adds " medicine " growth in first 24 hours.With after medicine, at 37 DEG C, through cultivation in 48 hours, by using trypanblue exclusion method (referring to reference book Roper, P.R.; Drewinko, B.Cancer Res.1976,36,2182-2188.) assess cell viability.
Human breast cancer cell MCF-7, KB cell KB, people's liver cancer Hep G2 and human colon cancer cell HT-29, these clones are cultivated the foetal calf serum (FBS) at 37 DEG C of 10% non-dialysis, in substratum, add the L-glutaminate of 2mM, in the DMEM substratum of penicillin 100 units/mL and 10 μ g/mL Streptomycin sulphates.
Suppress experiment for growth of tumour cell, it is 5 × 10 that above-mentioned cell is inoculated in a density 4in 24 orifice plates of individual cells/well and be placed to before medicine 24 hours.At 37 DEG C after 72 hours cultivate with medicine, then carry out the described methylene blue tests of people such as Finley (referring to reference book Finlay, G.J.; Baguley, B.C.; Wilson, W.R.Anal.Biochem.1984,139,272-277.).In brief, culture supernatant is inhaled to vacuum and cell by adding 0.2 milliliter of 0.5% methylenum coeruleum to dye in each hole.After 30 minutes, at room temperature, plate is inverted, to allow most dirt to drain.Binding dyeing immersion plate is not washed off in water.Plate, through dry air, stores, until need to be further processed.Dyeing cell by add respectively the dissolving of 0.2 milliliter of 1% sarcosyl in every hole, be placed on 37 DEG C 5 hours.From every hole of 24 orifice plates, shift 0.1 milliliter of supernatant liquor in each hole of 96 orifice plates.Read UV absorbancy at 595nm wavelength place by microplate reader.
Table 2 Compound C 16h 17n 3o 2half effective inhibition concentration (μ M) to tumour cell
From table 2, Compound C 16h 17n 3o 2multiple different tumor cell line is all shown to have certain restraining effect, wherein to people's acute leukemia cells HL60, people's chronic leukemia cell K562, human breast cancer cell MCF-7, KB cell KB, the IC of people's liver cancer Hep G2 and human colon cancer cell HT-29 50value is respectively 0.28,0.46,2.26,1.13,1.02 and 8.48 μ M.Therefore can be used for preparing antitumor drug.
The present invention provides new lead compound for developing new antitumour drug.
Below the preferred embodiment of the invention is illustrated, but the invention is not limited to described embodiment, those of ordinary skill in the art also can make all modification being equal to or replacement under the prerequisite without prejudice to the invention spirit, and the modification that these are equal to or replacement are all included in the application's claim limited range.

Claims (6)

1. aaptamine alkaloid compound or its pharmaceutical salts, its chemical structure is as shown in formula I:
2. a kind of aaptamine alkaloid compound according to claim 1 or its pharmaceutical salts, is characterized in that, described pharmaceutical salts is organic acid salt, inorganic acid salt and alkali salt.
3. a kind of aaptamine alkaloid compound according to claim 2 or its pharmaceutical salts, is characterized in that, described mineral acid refers to hydrochloric acid, sulfuric acid, phosphoric acid, bisphosphate, Hydrogen bromide or nitric acid; Described organic acid refers to acetic acid, toxilic acid, fumaric acid, tartrate, succsinic acid, lactic acid, tosic acid, Whitfield's ointment or oxalic acid; Described alkali refers to lithium hydroxide, sodium hydroxide, calcium hydroxide, potassium hydroxide, ammoniacal liquor, sodium carbonate, sodium bicarbonate.
4. a preparation method for aaptamine alkaloid compound as claimed in claim 1, is characterized in that, this preparation method comprises:
A, prepare total extract:
After dry thin sponge Aaptos aaptos is pulverized, with 95% ethanol cold soaking extraction, obtain extracting solution, extracting solution is concentrated to obtain to medicinal extract, add methylene dichloride to extract, obtain methylene dichloride total extract;
B, separation and purification:
1. prepare crude extract: by 90% methyl alcohol suspendible for methylene dichloride total extract, after normal hexane degreasing, add water the methanol concentration of suspension is adjusted to 60%, with dichloromethane extraction, concentrated extract obtains methylene dichloride crude extract;
2. separation and purification: by methylene dichloride crude extract through vacuum liquid chromatography (VLC), with methyl alcohol: methylene dichloride=100:1,80:1,60:1,50:1,30:1,20:1,10:1,8:1,5:1,1:1,0:1 is that solvent carries out gradient elution, and according to TLC thin-layer chromatography, colour developing merges similar flow point, obtains 7 component Fr.A – G;
3. component Fr.D is carried out to vacuum liquid chromatography (VLC), with methyl alcohol: methylene dichloride=60:1,50:1,30:1,15:1,10:1,8:1,5:1,0:1 is that solvent carries out gradient elution, and according to TLC thin-layer chromatography, colour developing merges similar flow point, obtains 7 component Fr.D1 – D7;
4. component Fr.D3 component is carried out to positive, reversed-phase column chromatography repeatedly, finally by RP-HPLC, condition is 50% acetonitrile/water, flow velocity 2mL/min, and detection wavelength is 244nm, retention time is 16.3 minutes, to obtain final product.
5. an aaptamine alkaloid compound as claimed in claim 1 or its pharmaceutical salts are in the application of preparing in antitumor drug.
6. aaptamine alkaloid compound according to claim 5 or its pharmaceutical salts are in the application of preparing in antitumor drug, it is characterized in that, described tumour behaviour acute leukemia cells HL60, people's chronic leukemia cell K562, human breast cancer cell MCF-7, KB cell KB, people's liver cancer Hep G2, or human colon cancer cell HT-29.
CN201410180478.7A 2014-04-30 2014-04-30 A kind of aaptamine alkaloid compound extracted from thin sponge and the application in preparing antineoplastic thereof Expired - Fee Related CN103936733B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018129904A1 (en) * 2017-01-13 2018-07-19 上海交通大学医学院附属仁济医院 Aaptamine alkaloid derivative, synthesis method therefor and application

Citations (1)

* Cited by examiner, † Cited by third party
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US20050187240A1 (en) * 2004-02-23 2005-08-25 The Arizona Board Of Regents, Acting For And On Behalf Of The Arizona State University Aaptamine and isoaaptamine and structural modifications thereof

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US20050187240A1 (en) * 2004-02-23 2005-08-25 The Arizona Board Of Regents, Acting For And On Behalf Of The Arizona State University Aaptamine and isoaaptamine and structural modifications thereof

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018129904A1 (en) * 2017-01-13 2018-07-19 上海交通大学医学院附属仁济医院 Aaptamine alkaloid derivative, synthesis method therefor and application
CN108299430A (en) * 2017-01-13 2018-07-20 上海交通大学医学院附属仁济医院 Benzodiazepine naphthalenes alkaloid and its synthetic method and application
CN108299430B (en) * 2017-01-13 2020-09-18 上海交通大学医学院附属仁济医院 Benzodiazanaphthyridine alkaloid and synthesis method and application thereof
US10799495B2 (en) 2017-01-13 2020-10-13 Renji Hospital, Shanghai Jiao Tong University School Of Medicine Aaptamine alkaloid derivatives and synthesis method and application thereof

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